The major scientific goals of this proposal are to determine the molecular mechanisms controlling inter-individual variability in inflammatory responses to bacterial products, to characterize the role of specific genes in determining this variability, and to determine whether nucleotide variability within these genes explains a portion of the variability seen in the clinical syndromes such as sepsis and ALI/ARDS. The primary hypothesis behind this proposal is that genetic variation that influences in vitro inflammatory responses to bacterial products will influence clinical outcomes in the severe inflammation seen in sepsis and ALI/ARDS. The proposed studies will employ inflammatory responses to bacterial lipopolysaccharide (LPS) ex vivo, an intermediate phenotype likely to contribute a portion of the risk of an individual to the development of sepsis and ALI/ARDS, as a probe to study this variability. Studies in Aim 1 will use oligonucleotide arrays and proteome-level analysis to determine differences in gene and protein expression between normal individuals who show "hyper" and "hypo"-responsive (lps[high] and lps[low]) cytokine responses to LPS ex vivo. In Aim 2, we propose a classical twins study to estimate the heritable and environmental components to LPS-induced cytokine responses. In Aim 3 we will test for association between SNP haplotypes within putative LPS-response genes and the ex vivo cytokine responses. In Aim 4, SNP haplotypes within LPS-response genes identified as being associated with the inflammatory response in Aim 3 will be tested in a clinical population of patients with sepsis and ALI/ARDS for association with clinical outcomes. It is hoped that identification of SNP haplotypes that confer increased (or decreased) risk for adverse outcomes in septic shock and ARDS will allow the prospective identification of patients who will benefit from experimental interventions. Furthermore, the algorithms developed through these studies will be applicable to inflammatory responses to other bacterial products that may contribute to the risk for development of sepsis and ALI/ARDS.